The class II major histocompatibility (MHC) antigens play a critical role in regulating the cellular immune response. In particular, the appropriate constitutive and inducible expression of class II MHC molecules are essential for normal immune response, whereas aberrantly high or low expression has been correlated with various autoimmune diseases (Massa et al., Proc. Natl. Acad. Sci USA 84, 4219-4223 (1987)) and a type of severe combined immunodeficiency disease (SCID) known as the Bare Lymphocyte Syndrome (BLS) (Griscelli et al., Immunodeficiency Rev. 1, 135-53 (1989)). Additionally, the class II MHC antigens are known to play a crucial role in causing organ transplant rejections.
Recognition of class II MHC by self T cells is a crucial step in most cell-mediated immunity. The process by which class II MHC antigens are recognized by T cells is called antigen presentation. Antigen presentation requires both the structural proteins, class II MHC molecules, which form the actual transplantation antigens recognized by the T cells, and molecules that are necessary for the targeting and proper function of class II MHC molecules (the li and DMA/DMB molecules).
The primary regulation of both constitutive and interferon-.gamma. (IFN-.gamma.)-induced class II MHC antigen gene expression occurs at the transcriptional level. Figueiredo et al., J. Immunol. 143, 3781-3786 (1989). Expression of the recently identified MHC class II transactivator, CIITA, closely parallels class II MHC antigen gene expression. Steimle et al., Cell 75, 135-46 (1993). It has also been shown that CIITA is induced by IFN-.gamma., and transfection of CIITA alone into cells is sufficient to activate class II MHC, li, and DM genes. See, e.g., Chin et al., Immunity 1, 679 (1994); Chang et al., J. Exper. Med. 180, 1367-1374 (1994); Steimle et al., Science 265, 106-08 (1994). CIITA transcript is expressed constitutively in class II MHC-positive cells; however, it can be induced in certain cell types such as fibroblasts, macrophages, and glioblastoma cells upon treatment with IFN-.gamma.. See Chang et al., supra; Steimle et al. (1994), supra, 106-08. The kinetics of CIITA induction by IFN-.gamma. precedes the induction of class II MHC transcripts, and introduction of CIITA alone into a number of cell types is sufficient to activate class II MHC antigen genes.
The N-terminus of the CIITA protein contains an acidic domain (amino acids 30-160), followed by domains rich in proline (amino acids 163-195), serine (amino acids 209-257), and threonine (amino acids 260-322). Steimle et al., 1993, supra. An acidic domain has been found in many transcription factors and has been shown to interact with basal transcriptional machinery in vitro and in vivo. See, e.g., Schmitz et al., J. Biol. Chem. 270, 7219-7226 (1995); Tong et al., Proc. Natl. Acad. Sci. USA 92, 3259-3263 (1995). However, it is likely that the acidic domain alone is not sufficient to activate the class II MHC promoter in CIITA, and that the acidic domains of other transcription factors behave differently from the CIITA acidic domain. Zhou et al., Immunity 2, 545-553 (1995). Analysis of the primary amino acid sequence of CIITA does not show any homology to known conserved DNA-binding motif of transcription factors, and in vitro translated CIITA apparently does not interact with DNA. Steimle et al. (1993), supra.
CIITA is now recognized as a "master control" molecule that transactivates all class II MHC genes, as well as genes necessary for the function of class II MHC molecules. In total, CIITA regulates at least seventeen genes, all of which are involved in immune activation. Because CIITA plays a central role in inducing expression of the class II MHC genes and orchestrating helper T cell activation, CIITA is implicated in the etiology of AIDs, transplant rejection, and autoimmune disease states (e.g., lupus, arthritis, diabetes, and multiple sclerosis). Accordingly, the present invention responds to a need in the art for improved methods of modulating immune responsiveness, in particular class II MHC antigen expression and helper T cell activation.